Some of the common approaches to cancer treatment include surgery, radiation therapy, and chemotherapy. Radiation therapy and chemotherapy are effective if they are capable of killing the tumor cells; i.e., when they act as cytotoxic agents. Typically, the response to radiation therapy or chemotherapy is monitored by magnetic resonance imaging (MRI) of the tumor, wherein a decrease in tumor size is indicative of positive response to treatment.
MRS has been proposed as a tool for obtaining information on cellular metabolism; see, for example, Norfray, J. et al., Ch. 110 in Pediatric Neurosurgery, 4th ed., McLone, D. G., et al. (Eds), W.B. Saunders Co. (2001). MRS also has been proposed for diagnosing the treatment response of tumors with cytotoxic agents; see, for example, Fulham, M. J., et al., Radiology, 185, 675-686 (1992), which discloses that brain tumor metabolism was studied with 1H MRS before and after treatment with radiation therapy. MRS permits non-invasive examination of metabolic characteristics of human cancers in a clinical environment. Accessible nuclei include 31P, 13C, 1H, and 23Na. 31P MRS contains information about energy status (phosphocreatine, inorganic phosphate, and nucleoside triphosphates), phospholipids metabolites (phosphomonoesters and phosphodiesters), intracellular pH (pH NMR), and free cellular magnesium concentration (Mg2+ f). Water-suppressed 1H MRS shows total choline, total creatine, lipids, glutamate, inositols, lactate, and the like. Negendank, W., NMR in Biomedicine, 5, 303-324 (1992).
Further, U.S. Pat. No. 6,681,132 (Katz et al.) discloses a method for determining the effectiveness of chemotherapy comprising administering a dose of a cytotoxic antineoplastic agent to a subject prior to surgical removal of a cancerous tumor, acquiring magnetic resonance data from the subject, and determining whether the treatment has affected the population of a nuclei, particularly 23Na. Negendank, W., supra, provides a review of various studies of human tumors by MRS.
See also Ross, B. et al., The Lancet, 641-646 (1984) discusses monitoring response to cytotoxic chemotherapy of intact human tumors by 31P MRS; Griffiths, J. R. et al., The Lancet, 1435-36, Jun. 25, 1983 discloses the use of 31P MRS to follow the progress of a human tumor during chemotherapy with doxorubicin; Ross, B. et al., Arch. Surg., 122, 1464-69 (1987) discloses the monitoring of chemotherapeutic treatment response of osteosarcoma and other neoplasms of the bone by 31P MRS; and Norfray, J. F. et al., J. Computer Assisted Tomography, 23(6), 994-1003 (1999) discloses an MRS study of the neurofibromatosis type 1 intracranial lesions.
More recently, peptide inhibitors, e.g., cell surface receptor inhibitors have been proposed for cancer treatment. See, for example, Blackledge, G. et al., British J. Cancer, 90, 566-572 (2004), which discloses that the epidermal growth factor receptor (EGFR) is a promising target for cancer therapy and that most advanced in development are the EGFR tyrosine kinase inhibitors (TKI's) gefitinib (Iressa, ZD 1839) and erlotinib (Tarceva, OSI-774), and the monoclonal antibody cetuximab (Erbitux, IMC-C225); Katz, A. et al., British J. Cancer, 89 (suppl. 2) S15-S18 (2003), which discloses the quality-of-life benefits and evidence of antitumor activity for patients with brain metastases treated with gefitinib; and Ranson, M. et al., J. Clin. Oncol., 20, 2240-50 (2002) which discloses that gefitinib is well tolerated and active in patients with solid, malignant tumors. However, the peptide receptor inhibitors have a positive response in only 15 to 50% of the patients treated.
The peptide inhibitors are cytostatic rather than cytotoxic; accordingly, classical signs of treatment response, e.g., decreased tumor size or decreased enhancement, common with cytotoxic agents, may not be present with cytostatic peptide inhibitors. Accordingly, classical imaging techniques such as MRI alone may not be suitable or adequate to monitor treatment response.
While MRS is effective as a tool for monitoring treatment response, the disclosures in the art show that it has been applied to monitor the response to cytotoxic agents (radiation and chemotherapy). In many cases, a detectable change in tumor size is observed only after a significantly long period of time, for example, after treatment for a period of about 3 months or more. Such long periods of time could be harmful to the patient, especially if the treatment has not been effective or only partially effective, such as, for example, treatments involving the use of peptide inhibitors; during this long period of time, tumor cells could multiply or metastasize, and lead to worsening of the patient's condition.
The foregoing shows that there exists a need for a method where an early treatment response can be monitored, especially where the treatment involves cell surface receptor inhibitors. Accordingly, the present invention provides such a method. This and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.